Randomized Controlled Trial Comparing Methotrexate or Leflunomide with Targeted Therapy Versus Triple Therapy in Rheumatoid Arthritis Patients Unresponsive to Methotrexate or Leflunomide

The primary objective of this randomized controlled clinical trial is to evaluate the efficacy of **targeted therapies** compared to triple therapies in patients with **Rheumatoid Arthritis** (RA) who exhibit an insufficient response to methotrexate or leflunomide. This is clinically relevant as it aims to determine the most effective treatment strategy for improving patient outcomes in this population, potentially leading to optimized therapeutic approaches for RA management.

Secondary objectives include:

• Comparing the safety profile of the two treatment strategies.
• Assessing the drug retention rate and treatment adherence at inclusion, 6, and 12 months.
• Evaluating changes in the Clinical Disease Activity Index (CDAI) at 3, 6, 9, and 12 months.
• Comparing the Disease Activity Score 28 (DAS 28) with C-reactive protein (CRP) at 3, 6, 9, and 12 months.
• Assessing the American College of Rheumatology (ACR) criteria and boolean remission at 3, 6, 9, and 12 months.
• Evaluating radiographic progression between 0 and 12 months.
• Comparing changes in comedications at 3, 6, 9, and 12 months.
• Assessing patient quality of life and fatigue in the two groups.
• Evaluating the impact of RA on sexuality in the two groups.
• Assessing and comparing medico-economic aspects in the two groups.

The clinical trial involves a total of **16 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects, aged 18 years and older, who meet the EULAR/ACR 2010 criteria for rheumatoid arthritis. Participants are required to have a DAS28-CRP score greater than 3.2 and must have shown an insufficient response to methotrexate or leflunomide treatment. The trial population was selected based on specific inclusion criteria, including the presence of RA radiographic erosions, serum rheumatoid factor, or anti-Cyclic Citrullinated Peptide (Anti-CCP). Participants must provide written informed consent and be affiliated with a social insurance system. Women of childbearing potential are required to have a negative β-HCG assay and must use an effective method of birth control during and after the study. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, ensuring comprehensive ethical considerations are in place.

The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy of targeted therapies compared to triple therapies in patients with **rheumatoid arthritis** who have shown an insufficient response to **methotrexate** or **leflunomide**. The trial aims to determine whether targeted therapies are more effective in achieving low disease activity, as measured by the DAS28-CRP score, and reducing the daily dose of prednisone. The study is expected to last for approximately 13 years, with an estimated recruitment start date in March 2016 and an estimated end date in March 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease activity, and previous treatment response. Following the inclusion visit, participants will be randomized into one of the treatment groups. Follow-up visits will occur at 3, 6, 9, and 12 months to monitor disease activity, medication adherence, and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including the DAS28-CRP score, serious adverse events rate, and blood concentrations of the study drugs.

The expected length of participant involvement is 12 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will involve the administration of various study drugs, including **etanercept**, **tocilizumab**, **baricitinib**, **abatacept**, **upadacitinib**, **infliximab**, **sarilumab**, **certolizumab pegol**, **golimumab**, **rituximab**, **adalimumab**, **tofacitinib**, **sulfasalazine**, **filgotinib**, and **hydroxychloroquine sulfate**, through routes such as **oral**, **subcutaneous**, and **intravenous** use. The maximum treatment period for each drug is 12 months, with specific dosing regimens tailored to each medication.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with rheumatoid arthritis. **Etanercept** is provided as a powder and solvent for solution for injection, administered via subcutaneous use. The maximum daily dose is 50 mg, with a total dose not exceeding 2600 mg over a 12-month period. **Tocilizumab** is available as a concentrate for solution for infusion, administered either intravenously or subcutaneously, with a maximum daily dose of 800 mg and a total dose of 9600 mg over the same period.

**Baricitinib** is administered orally in the form of film-coated tablets, with a maximum daily dose of 4 mg and a total dose of 1460 mg over 12 months. **Abatacept** is provided as a powder for concentrate for solution for infusion, administered intravenously or subcutaneously, with a maximum daily dose of 12.5 mg/kg and a total dose of 187.5 mg/kg over the treatment period. **Upadacitinib** is administered orally as a prolonged-release tablet, with a maximum daily dose of 15 mg and a total dose of 5475 mg over 12 months.

**Methotrexate** is used in various forms: as a solution for injection in a pre-filled syringe, with a maximum daily dose of 25 mg and a total dose of 1300 mg over 12 months, and as tablets for oral use with the same dosing schedule. **Infliximab** is provided as a powder for concentrate for solution for infusion, administered intravenously, with a maximum daily dose of 7.5 mg/kg and a total dose of 49.5 mg/kg over the treatment period.

**Sarilumab** is administered as a solution for injection via subcutaneous use, with a maximum daily dose of 200 mg and a total dose of 5200 mg over 12 months. **Certolizumab pegol** is provided as a solution for injection in a pre-filled syringe, administered subcutaneously, with a maximum daily dose of 400 mg and a total dose of 6000 mg over the treatment period. **Golimumab** is administered as a solution for injection in a pre-filled pen, with a maximum daily dose of 100 mg and a total dose of 1200 mg over 12 months.

**Rituximab** is available as a concentrate for solution for infusion, administered intravenously or subcutaneously, with a maximum daily dose of 1000 mg and a total dose of 4000 mg over the treatment period. **Adalimumab** is administered as a solution for injection in a pre-filled syringe, with a maximum daily dose of 40 mg and a total dose of 1040 mg over 12 months. **Leflunomide** is provided as a film-coated tablet for oral use, with a maximum daily dose of 100 mg and a total dose of 7540 mg over the treatment period.

**Tofacitinib** is administered orally as a film-coated tablet, with a maximum daily dose of 11 mg and a total dose of 4015 mg over 12 months. **Sulfasalazine** is provided as a gastro-resistant tablet for oral use, with a maximum daily dose of 2 g and a total dose of 730 g over the treatment period. **Filgotinib** is administered orally as a film-coated tablet, with a maximum daily dose of 200 mg and a total dose of 73 g over 12 months.

**Hydroxychloroquine sulfate** is provided as a film-coated tablet for oral use, with a maximum daily dose of 600 mg and a total dose of 219 g over the treatment period. The trial also includes non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, which are not specified in the provided data. Participant compliance is monitored throughout the trial to ensure adherence to dosing schedules and administration routes.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is defined as achieving low disease activity, indicated by a Disease Activity Score 28 - C-reactive protein (DAS28-CRP) of less than 3.2, along with a daily dose of prednisone equivalent to or less than 7.5 mg, under the randomized strategy after a minimum follow-up period of 11 months. Secondary endpoints include a range of measures such as the rate of serious adverse events, blood concentrations of various drugs in the treatment groups, and several clinical and patient-reported outcomes.

Secondary endpoints will be evaluated at multiple time points, including at inclusion, 3, 6, 9, and 12 months. These include the Clinical Disease Activity Index (CDAI), DAS28-CRP score, and the 2010 ACR/EULAR classification criteria for rheumatoid arthritis, including ACR 20, 50, 70, and Boolean remission. Additionally, the Modified Sharp Van der Hejde score will be assessed at inclusion and at 12 months. Patient-reported outcomes will be measured using validated scales such as the SF36, Rapid, HAQ, RAID, and FACIT scores at specified intervals. The QUALISEX score will be evaluated at inclusion, 6 months, and 12 months. A medico-economic evaluation will also be conducted at inclusion, 3, 6, 9, and 12 months.